Project Summary Periodontal disease, which results from bacterial infection and inflammation of the gums and bone that surround and support the teeth, affects nearly half of US adults over 30, with ~9% having severe periodontitis. The hallmark of periodontitis is destruction of alveolar bone, resulting ultimately in extended tooth loss and oral disability. Periodontitis is a major oral health problem, particularly among the elderly, that increases the risk for systemic diseases, including atherosclerosis, rheumatoid arthritis, and diabetes mellitus. The general goals of this grant are to determine the role of newly discovered gingival solitary chemosensory cells (gSCCs) in protecting against periodontitis, to identify the receptors, signaling pathways and effectors involved in innate immunity evoked by gSCC activation, and to identify compounds that activate gSCCs to harness host innate immunity to reduce periodontitis. Periodontitis results from polymicrobial dysbiosis, which perturbs the ecologically balanced oral microbiota, and from disruption of the host innate immunity, which also contributes to the destruction of periodontal tissue. While much is known about how microbes and host immunity contribute to periodontitis, it is still unclear which gingival cells protect against the disease. Recent studies in several types of mucosae have identified taste cell-like SCCs as specialized chemosensitive sentinel cells that detect bacteria and evoke host innate immune responses. Most recently, we have identified gSCCs in the mouse gingival junctional epithelium that is part of the epithelial barrier protecting against bacterial infection of the tooth and surrounding gingiva. gSCCs express bitter taste receptors along with other taste transduction components, respond to bacterial signaling molecules, and trigger intrinsic innate immunity to protect against periodontitis. The experiments of this proposal study the role of gSCCs in gingival/tooth health to determine if gSCCs evoke innate immune responses that prevent overgrowth of oral bacteria in the gingival mucosa (Aim 1); identify the receptors and signaling components of gSCCs and the mechanism by which gSCCs promote gingival release of antimicrobial peptides and inflammatory cytokines (Aim 2); and determine if ?on demand ?activation of the gSCC signaling pathway reduces periodontitis (Aim 3). Understanding the initiating receptors and underlying mechanisms of these responses may lead to new approaches to promote oral health and treat periodontitis.